1-azatricyclic-4-benzylpiperazines

ABSTRACT

Disclosed are 1-Azatricyclic-4-benzylpiperazine compounds which are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. Pharmaceutical compositions, including packaged pharmaceutical compositions, are further provided. Compounds of the invention are also useful as probes for the localization of GABAA receptors in tissue samples.

This is a continuation of application Ser. No. 09/596,020 now U.S. Pat.No. 6,294,530, filed Jun. 14, 2000, which claims priority fromapplication Ser. No. 60/139,135, filed Jun. 14, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 1-azatricyclic-4-benzylpiperazines, and tocompounds that bind to dopamine receptors. This invention also relatesto pharmaceutical compositions comprising such compounds and also to thetreatment of central nervous system (CNS) diseases, particularly thetreatment or prevention of psychotic disorders such as to schizophrenia.Additionally this invention relates to the use of compounds as probesfor the localization of dopamine receptors in tissue sections.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has been identified andcloned. Its unique localization in limbic brain areas and itsdifferential recognition of various antipsychotics suggest that the D₄receptor may play a major role in the etiology of schizophrenia. Thedopamine D₄ receptor shares sequence homology with dopamine D₂ and D₃receptors, however the D₄ receptor possesses a unique pharmacologicalprofile. Selective D₄ antagonists, including the marketed antipsychoticchlozapine, are considered effective antipsychotics free from theneurological side effects displayed by conventional neuroleptics.Compounds that possess a 10-fold or more higher affinity for dopamine D₄receptors than D₂ receptors are considered particularly desirable asantipsychotics.

Since dopamine D₄ receptors are concentrated in the limbic system whichcontrols cognition and emotion, compounds which interact with thesereceptors have utility in the treatment of cognitive disorders. Suchdisorders include the cognitive deficits which are a significantcomponent of the negative symptoms (social withdrawal andunresponsiveness) of schizophrenia. Other disorders involving memoryimpairment or attention deficit disorder can also be treated withcompound that interact specifically with the dopamine D₄ receptorsubtype.

SUMMARY OF THE INVENTION

This invention provides 1-azatricyclic-4-benzylpiperazine compounds thatbind, preferably with high affinity and selectivity, to the D₄ receptorsubtype, including human D₄ receptors. These compounds are thereforeuseful in treatment of a variety of neuropsychological disorders, suchas, for example, schizophrenia, psychotic depression and mania. Otherdopamine-mediated diseases such as Parkinsonism and tardive dyskinesiascan also be treated directly or indirectly by modulation of D₄receptors.

Thus, the invention provides compounds of Formula I (shown below), andpharmaceutical compositions comprising compounds of Formula I.

The invention further comprises methods of treating patients sufferingfrom CNS disorder with a therapeutically effective amount of a compoundof the invention. The patient may be a human or other mammal. Treatmentof humans, domesticated companion animals (pets) or livestock animalssuffering from CNS disorder with a therapeutically effective amount of acompound of the invention is encompassed by the invention. Particularlymethods for the treatment and/or prevention of neuropsychological oraffective disorders, for example, schizophrenia, mania, dementia,depression, anxiety, compulsive behavior, substance abuse, memoryimpairment, cognitive deficits, Parkinson-like motor disorders, e.g.,Parkinsonism and dystonia, and motion disorders related to the use ofneuroleptic agents are included. In addition, the compounds of theinvention are useful in treatment of depression, memory-impairment orAlzheimer's disease by modulation of D₄ receptors which selectivelyexist in limbic areas known to control emotion and cognitive functions.Further, the compounds of the present invention are useful for thetreatment of other disorders that respond to dopaminergic blockade,e.g., substance abuse and obsessive compulsive disorder. These compoundsare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents.

Accordingly, a broad aspect of the invention is directed to compounds ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein

A represents phenyl optionally substituted with up to four groupsindependently selected from halogen, hydroxy, amino, mono- ordi(C₁-C₆)hydrocarbylamino, aminosulfonyl, C₁-C₆hydrocarbylaminosulfonyl, di(C₁-C₆)hydrocarbylaminosulfonyl, cyano,nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C₁-C₆ hydrocarbyl,trifluoromethoxy, C₃-C₆ cyclohydrocarbyl, and C₁-C₆ alkoxy;

R₅ and R₆ are the same or different and represent hydrogen or C₁-C₆hydrocarbyl; and

R₂ represents hydrogen, halogen, hydroxy, amino, mono- ordi(C₁-C₆)hydrocarbylamino, aminosulfonyl, C₁-C₆hydrocarbylaminosulfonyl, di(C₁-C₆)hydrocarbylaminosulfonyl, cyano,nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C₁-C₆ hydrocarbyl,trifluoromethoxy, C₃-C₆ cyclohydrocarbyl, or C₁-C₆ alkoxy; and

n is 0, 1, or 2.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses the compounds of Formula I described above.

In preferred compounds of formula I,

A represents phenyl optionally substituted with up to four groupsindependently selected from halogen, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, aminosulfonyl C₁-C₆ alkylaminosulfonyl, di (C₁-C₆)alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl,(C₁-C₆) alkyl, trifluoromethoxy, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy;

R₅ and R₆ are the same or different and represent hydrogen or C₁-C₆alkyl; and

R₂ represents hydrogen, halogen, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, aminosulfonyl, C₁-C6 alkylaminosulfonyl,di(C₁-C₆)alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethoxy, C₃-C₆ cycloalkyl, orC₁-C₆ alkoxy; and n is 0, 1, or 2.

In other preferred compounds of Formula I, n is 2;

A represents phenyl optionally substituted with up to four groupsindependently selected from halogen, hydroxy, amino, mono- or di(C₁-C₆)alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl,(C₁-C₆)alkyl, trifluoromethoxy, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy;

R₅ and R₆ are the same or different and represent hydrogen or C₁-C₆alkyl; and

R₂ represents hydrogen, halogen, hydroxy, amino, mono- or di (C₁-C₆)alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl,(C₁-C₆)alkyl, trifluoromethoxy, C₃-C₆ cycloalkyl, or C₁-C₆ alkoxy.

More preferred compounds of Formula I are those where A is a group ofthe formula:

where R₃ and R₄ independently represent hydrogen, halogen, hydroxy,amino, aminosulfonyl, C₁-C₆ alkylaminosulfonyl,di(C₁-C₆)alkylaminosulfonyl, cyano, nitro, trifluoromethoxy, C₁-C₆alkyl, or C₁-C₆ alkoxy.

These more preferred compounds are represented by Formula II herein.

In preferred compounds of Formula II, R₃ and R₄ are the same ordifferent and are C₁-C₃ alkyl, chloro, fluoro, bromo, or C₁-C₃ alkoxy.More preferably, in compounds of Formula II at least one of R₃ and R₄ isattached at the ortho or para position of the phenyl ring. Still morepreferably, R₂ in Formula II is hydrogen, fluoro, chloro, or C₁-C₂alkyl.

In other preferred compounds of II, R₂ is hydrogen. Such compounds aredesignated as compounds of Formula II-A hereinafter. In these compounds,R₃ and R₄ are the same or different and are C₁-C₃ alkyl, chloro, fluoro,bromo, or C₁-C₃ alkoxy. Preferably compounds of Formula II-A are thosewhere at least one of R₃ and R₄ is in the ortho or para position of thephenyl ring. More preferred compounds of II-A are those wherein R₅ andR₆ independently represent hydrogen or C₁-C₂ alkyl. Still other morepreferred compounds of II-A are those wherein at least one of R₅ and R₆is methyl. Particularly preferred compounds of II-A are those where bothR₅ and R₆ are methyl. Other particularly preferred compounds of FormulaII-A are those where R₅ is methyl and R₆ is hydrogen.

The compounds of this invention may contain one or more asymmetriccenters, e.g., carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,mixtures of diastereomers, or racemates or resolved enantiomers. Singleenantiomers can be obtained as pure compounds or in enantiomeric excessby asymmetric synthesis or by resolution of the racemate. Resolution ofthe racemate can be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutically acceptable salts include, but are not limitedto salts of inorganic acids such as hydrochloric, sulfuric, phosphoric,diphosphoric, hydrobromic, and nitric or salts of organic acids such asformaic, citric, malic, maleic, fumaric, tartanic, succinic, acetic,lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic,salicylic and stearic. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses prodrugs of the compounds ofFormula I, e.g., acylated compounds and esters of Formula I. Thoseskilled in the art will recognize various synthetic methodologies whichmay be employed to prepare non-toxic pharmaceutically acceptableaddition salts and prodrugs of the compounds encompassed by Formula I.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers. The invention includesall tautomeric forms of a compound.

Representative compounds of the invention are shown below in Table 1.

TABLE 1

This invention provides 1-azatricyclic-4-benzylpiperazine compounds thatbind with high affinity to dopamine receptors, particularly dopamine D₄receptors, including human dopamine D₄ receptors. This invention alsoincludes compounds that bind with high selectivity to dopaminereceptors, particularly dopamine D₄ receptors, including human dopamineD₄ receptors. Without wishing to be bound to any particular theory, itis believed that the interaction of the compounds of the invention withthe dopamine D₄ receptor results in the pharmaceutical utility of thesecompounds.

The invention further comprises methods of treating patients sufferingfrom a CNS disorder with an amount of a compound of the inventionsufficient to alter the symptoms of the disorder.

The diseases, conditions and disorders that can be treated usingcompounds and compositions according to the invention include, but arenot limited to, schizophrenia, psychotic depression, mania, and theextrapyramidyl side effects associated with the use of a neurolepticagent. Other dopamine-mediated disease such as Parkinsonism and tardivedyskinesias can also be treat directly or indirectly by modulation ofdopamine receptors. Compounds of the invention are also useful in thetreatment of depression, memory-impairment or Alzheimer's disease bymodulation of D₄ receptors since these receptors are localized in areasknown to control emotion and cognitive functions.

The invention also provides pharmaceutical compositions comprisingcompounds of the invention, including packaged pharmaceuticalcompositions, for treating disorders responsive to dopamine receptormodulation, especially dopamine D₄ receptor modulation, e.g., treatmentof schizophrenia, depression, tardive diskinesia or cognitive impairmentby dopamine D₄ receptor modulation. The packaged pharmaceuticalcompositions include a container holding a define quantity or unit dose,e.g., a therapeutically effective amount, of at least one compound ofthe invention and instructions (e.g., labeling) indicating how thecontained compound is to be used in the patient, e.g., for treating adisorder responsive to dopamine receptor modulation.

The present invention also pertains to methods of inhibiting the bindingof dopamine to dopamine D₄ receptors which methods involve contacting acompound of the invention with cells expressing dopamine D₄ receptors,wherein the compound is present at a concentration sufficient to inhibitdopamine binding to dopamine D₄ receptors in vitro. This method includesinhibiting the binding of dopamine to dopamine D₄ receptors in vivo,e.g., in a patient given an amount of a compound of Formula I that wouldbe sufficient to inhibit the binding of dopamine to dopamine D₄receptors in vitro. The amount of a compound that would be sufficient toinhibit the binding of dopamine to the dopamine D₄ receptor may bereadily determined via a dopamine receptor binding assay, such as theassay described in Example 3. The dopamine receptors used to determinein vitro binding may be obtained from a variety of sources, for examplefrom preparations of rat striatal homogenates or from cells expressingcloned human or monkey dopamine D₄ receptors.

The compounds of this invention and labeled derivatives thereof are alsouseful as standards and reagents in determining the ability of apotential pharmaceutical agent to bind to the dopamine D₄ receptor.

Radiolabeled derivatives of the compounds of this invention are alsouseful as radiotracers for positron emission tomography (PET) imaging orfor single photon emission computerized tomography (SPECT).

Definitions

Where the compounds of the present invention have asymmetric centers,the invention includes all of the optical isomers and mixtures thereof.

Compounds with carbon-carbon double bonds may occur in Z- and E-forms,and all the isomers of such compounds are included in the invention.

When any variable (e.g. C₁₋₆ alkyl, C₁₋₈ alkyl, A, R₂, R₅, or R₆) occursmore than one time in any formula herein, its definition at eachoccurrence is independent of its definition at every other occurrence.

By “C₁-C₆ alkyln” in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms. Examples of alkyl groupsinclude, for example, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl.

By “C₁-C₆ hydrocarbyl” in the present invention is meant straight orbranched chain alkyl groups having 1-6 carbon atoms, optionallycontaining one or more carbon-carbon double or triple bonds. Examples ofhydrocarbyl groups include, for example, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, 2-pentene,and propargyl. When reference is made herein to C₁-C₆ hydrocarbylcontaining one or two double or triple bonds it is understood that atleast two carbons are present in the alkyl for one double or triplebond, and at least four carbons for two double or triple bonds.

By “C₁-C₆ alkoxy” or “lower alkoxy” in the present invention is meant analkyl group of indicated number of carbon atoms attached to the parentmolecular moiety through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy. Preferred alkoxy groups herein are C₁-C₄ alkoxy groups.

The term “cycloalkylalkyl,” as used herein, refers to a C₃-C₇ cycloalkylgroup attached to the parent molecular moiety through an alkyl group, asdefined above. Examples of cycloalkylalkyl groups includecyclopropylmethyl and cyclopentylethyl.

The term “halogen” indicates fluorine, chlorine, bromine, or iodine.

Pharmaceutical Preparations

Those skilled in the art will recognize various synthetic methodologiesthat may be employed to prepare non-toxic pharmaceutically acceptableprodrugs of the compounds encompassed by Formula I. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable solvents that may be used to prepare solvates of thecompounds of the invention, such as water, ethanol, mineral oil,vegetable oil, and dimethylsulfoxide.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Oral administration in theform of a pill, capsule, elixir, syrup, lozenge, troche, or the like isparticularly preferred. The term parenteral as used herein includessubcutaneous injections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of Formula I may be administered parenterally in a sterilemedium. The drug, depending on the vehicle and concentration used, caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as local anesthetics, preservatives and buffering agentscan be dissolved in the vehicle.

For administration to non-human animals, the compounds of Formula I maybe added to the animals feed or drinking water. It will be convenient toformulate these animal feed and a drinking water compositions so thatthe animal consumes an appropriate quantity, e.g., a therapeuticallyeffective amount, of the compound in its diet. It will also beconvenient to in present the compound in a composition as a premix foraddition to the feed or drinking water.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to in about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. For the treatmentof schizophrenia, depression, or cognitive impairment a dosage regimenof 1 or 2 times daily is particularly preferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention will have desirable pharmacologicalproperties that include, but are not limited to, oral bioavailability,low toxicity, low serum protein binding and desirable in vitro and invivo half-lifes. Penetration of the blood brain barrier for compoundsused to treat CNS disorders is necessary, while low brain levels ofcompounds used to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocytes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lifes of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Preparation of Compounds

A representative synthesis of the compounds of the invention ispresented in Scheme I. Those having skill in the art will recognize thatthe starting materials and reaction conditions may be varied andadditional steps employed to produce compounds encompassed by thepresent invention, as demonstrated by the following examples. In somecases, protection of reactive functionalities may be necessary toachieve some of the transformations. In general, the need for suchprotecting groups as well as the conditions necessary to attach andremove such groups will be apparent to those skilled in the art oforganic synthesis.

In Scheme I, R₂, R₃, R₄, R₅ and R₆ are as defined for Formula I. W isappropriate leaving group such as, for example, halogen or a sulfonateester.

The starting indolines (5) are either commercially available, known, orcapable of being prepared by the methods known in the art. Thus, toprepare compounds where R₅ and R₆ are alkyl, starting indoline (5) maybe prepared by the methods of Azadi-Ardakani (J. Chem. Soc. Perkin TransI. 1986, 1107). Azatricyclics 6 and 7 may be prepared according to themethods of Bass et al (J. Agri. Food Chem. 1981, 29, 576) or DeLombaert(Bioorg. Med. Chem. Lett. 1994, 7513). Preparation of intermediatescontaining an iodo leaving group (i.e., 8, where W=iodine) may becarried out by the method of Fisher (PCT application WO 95/16692). Othercompounds may be prepared by procedures analogous to those described inliterature.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference in theirentirety.

The invention is further illustrated by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLES Example 1

The following scheme represents the synthesis described below.

Compound 9. Indoline (23.8 g, 0.2 mol), succinic anhydride (20.0 g, 0.2mol) and triethylamine (40 mL) are combined in chloroform (200 mL) andstirred at room temperature for about sixteen hours. The solvent is thenremoved under reduced pressure and the product is precipitated by addingaqueous HCl solution (5%, 500 mL). After filtration, the filter cake iswashed with water and dried to give compound 9 (35.2 g, 80%) as anoff-white powder: ¹H NMR (300 MHz, CDCl₃) 2.76-2.81 (m, 4H), 3.23 (t,J=8.1 Hz, 2H), 4.09 (t, J=8.1 Hz, 2H), 7.04 (t, J=6.9 Hz, 1H), 7.18-7.22(m, 2H), 8.20 (d, J=8.4 Hz, 1H); MS (LC-MS) m/e 202 (M+H−18)₊.

Compound 10. To a solution of compound 9 (15.0 g, 0.068 mol) indichloroethane (250 mL) is added dimethylformamide (0.5 mL) and oxalylchloride (8 mL, 0.092 mol). The resulting solution is stirred for about1 h at room temperature, and then cooled to 0° C. with an ice bath. Asuspension of aluminum trichloride (36.5 g, 0.27 mol) in dichloroethane(100 mL) is poured into the reaction mixture. The ice bath is removedand the reaction mixture is heated to 50° C. for about 4 h. Additionalaluminum trichloride (9.0 g, 0.068 mol) is added and the heating iscontinued overnight. The reaction mixture is cooled to room temperatureand then poured on to ice. The resulting slurry is filtered and theproduct extracted several times with dichloromethane. The combineddichloromethane extracts are dried over sodium sulfate, filtered andconcentrated. The crude product is purified by chromatography on silicagel, eluting with 50% ethyl acetate in hexanes to yield 2.5 g (18%) ofcompound 10 as a light yellow powder. ¹H NMR (300 MHz, CDCl₃) 2.84-2.88(m, 2H), 2.92-2.96 (m, 2H), 3.16 (t, J=8.7 Hz, 2H), 4.25 (t, J=8.7 Hz,2H), 7.11 (t, J=7.8 Hz, 1H), 7.42 (dd, J=1.4, 7.1 Hz, 1H), 7.95 (d, 1H);MS (GC-MS) m/e 202 (M+H)⁺.

Compound 11. A mixture of compound 10 (2.5 g, 0.012 mol) and 10% Pd/C(2.5 g) in 20 mL of acetic acid is treated with hydrogen at about 50 psiovernight. The catalyst is filtered off and the solvent evaporated. Theresidue is partitioned between ethyl acetate (50 mL) and saturatedNaHCO₃. The aqueous layer is extracted twice with ethyl acetate and thecombined ethyl acetate layers are washed with brine, dried over Na₂SO₄,filtered and concentrated to give compound 11 (2.3 g, 100%) as anoff-white solid: ¹H NMR (300 MHz, CDCl₃) 1.96-2.04 (m, 2H), 2.79 (t,J=6.3 Hz, 2H), 2.97 (t, J=6.0 Hz, 2H), 3.05 (t, J=8.7 Hz, 2H), 4.13 (t,J=8.7 Hz, 2H); MS (GC-MS) m/e 188 (M+H)⁺.

5-[(4-Chlorobenzyl)piperazin-1-yl]-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine,Compound 12

To a 0° C. solution of compound 11 (0.9 g, 4.8 mmol) in dichloromethane(9 mL) is added of N,N,N′,N′-tetramethylethylenediamine (TMEDA) (2.10mL) and trimethylsilyl iodide (2.00 mL). After about 30 min, solidiodine (1.8 g) is added and the reaction mixture is stirred at 0° C. for40 min. A mixture of dichloromethane and excess aqueous sodium sulfiteis added to quench the reaction. The reaction mixture is extractedseveral times with dichloromethane and the combined extracts are washedwith brine, dried over Na₂SO₄, filtered and concentrated to give 1.40 gof crude product. An analytically pure sample can be prepared bychromatographing the crude product on silica gel, eluting with 25% ethylacetate in hexanes. ¹H NMR (300 MHz, CDCl₃) 1.82-1.92 (m, 1H), 2.14-2.25(m, 1H), 3.00-3.17 (m, 3H), 3.45-3.56 (m, 1H), 3.99-4.19 (m, 1H),4.21-4.28 (m, 1H), 5.24 (d, J=6.6 Hz, 1H, ICH), 6.90-7.09 (m, 3H).

The above crude product, p-chlorobenzylpiperizine (0.63 g, 0.003 mol)and K₂CO₃ (0.3 g) are refluxed in acetonitrile (4 mL) for about 1 h.After cooling, the reaction mixture is filtered, concentrated andpurified by chromatography on silica gel eluting with ethyl acetatefollowed by chloroform to yield compound 12 (1.1 g, 57% yield for twosteps). ¹H NMR (300 MHz, CDCl₃) 1.99-2.08 (m,1H), 2.20-2.30 (m, 1H),2.62 (bs, 4H), 2.82 (bs, 2H), 2.94-3.15 (m, 6H), 3.40 (d, J=8.5 Hz, 1H),3.57 (s, 2H), 3.89-3.99 (m, 1H), 4.25-4.32 (m, 1H), 6.88-7.07 (m, 3H),7.30-7.34 (m, 5H); MS (LC-MS) m/e 396 (M+H)⁺.

Example 2

The following compounds are prepared essentially according to theprocedures set forth above in Example 1:

(a)5-[(4-methylbenzyl)piperazin-1-yl]-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine(Compound 1). ¹H NMR (free base, 400 Hz, CDCl₃) δ 1.94-2.03 (m, 1H),2.17-2.19 (m,1H), 2.33 (s, 3H), 2.56-2.71 (m, 6H), 2.95-3.17 (m, 6H),3.35 (d, J=8.52 Hz, 1H), 3.47-3.55 (bs, 2H), 3.95-4.01 (m, 1H),4.22-4.27 (m, 1H), 6.86-7.06 (m, 3H), 7.12 (d, J=7.69 Hz, 2H), 7.24 (d,J=7.96 Hz, 2H); MS (LC-MS) m/e 376 (M+H)⁺.

(b)5-[(4-chlorobenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine(Compound 2). MS (LC-MS) m/e 424 (M+H)⁺.

(c)cis-5-[(4-chlorobenzyl)piperazin-1-yl]-2-methyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2, 1-jk][1]benzazepine(Compound 4A).

(d)trans-5-[(4-chlorobenzyl)piperazin-1-yl]-2-methyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine(Compound 4B).

Compounds 4A and 4B are prepared as a diastereomeric mixture (identifiedherein as Compound 4) by condensation of 1-(4-chlorobenzyl)piperazinewith diastereomeric2-methyl-5-chloro-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepinein the presence of base. The individual isomers may be separated bycolumn chromatography.

(e)5-[(2-methoxy-5-methylbenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine(Compound3). MS (LC-MS) m/e 434 (M+H)⁺.

¹H NMR (CDCl₃) δ 7.16 (s, 1H), 6.9-7.0 (m, 4H), 6.74 (d, J=9 Hz, 1H),3.77 (s, 3H), 3.54 (s, 2H), 3.25 (dd, J=9, 3 Hz, 1H), 2.8-3.0 (m, 6H),2.67-2.71 (m, 2H), 2.53 (bs, 4H), 2.27 (s, 3H), 2.2 (m, 1H), 2.1 (m,1H), 1.63 (s, 3H), 1.54 (s, 3H).

(f)5-[(2-methoxy-5-chlorobenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine(Compound13).

¹H NMR (CDCl₃) δ 7.36 (s, 1H), 7.15 (dd, J=9, 3 Hz, 1H), 6.9-7.0 (m,3H), 6.75 (d, J=9 Hz, 1H), 3.78 (s, 3H), 3.52 (s, 2H), 3.25 (dd, J=9, 3Hz, 1H), 2.8-3.0 (m, 6H), 2.69-2.74 (m, 2H), 2.52 (bs, 4H), 2.2 (m, 1H),2.1 (m, 1H), 1.64 (s, 3H), 1.54 (s, 3H).

(g)5-[(2-methoxy-4-methylbenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine(Compound 14).

¹H NMR (CDCl₃) δ 7.19 (d, J=7 Hz, 1H), 6.8-7.0 (m, 3H), 6.71 (d, J=7 Hz,1H), 6.66 (s, 1H), 3.78 (s, 3H), 3.51 (s, 2H), 3.22 (dd, J=9, 3 Hz, 1H),2.8-3.0 (m, 6H), 2.61-2.67 (m, 2H), 2.5 (bs, 4H), 2.32 (s, 3H), 2.2 (m,2H), 1.61 (s, 3H), 1.52 (s, 3H).

Example 3 Determination of D₂, D₄ and α₁ Receptor Binding Activity

The following assay is a standard assay for determining the bindingaffinity of compounds to dopamine D₄ and D₂ receptors.

Pellets of Chinese hamster ovary (CHO) cells containing recombinantlyproduced primate D₂, human D₄ and human α1 receptors are used for theassays. The sample is homogenized in 100 volumes (w/vol) of 0.05 M TrisHCl buffer containing 120 mM NaCl, 5 mM MgCl₂ and 1 mM EDTA at 4° C. andpH 7.4. The sample is then centrifuged at 30,000×g, resuspended andrehomogenized. The sample is then recentrifuged at 30,000×g, thesupernatant is removed and the final tissue sample is frozen until it isneeded. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HClbuffer containing 120 mM NaCl.

Incubations for dopaminergic binding are carried out at 25° C. andcontain 0.4 ml of tissue sample, 0.1 nM ³H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Nonspecific binding is defined as that binding found in the presence of1 μM spiperone; without further additions, nonspecific binding is lessthan 20% of total binding.

Norepinephrine al binding is carried out using ³H-prazosine as theligand. Nonspecific binding is determined in the presence of 1 μMprazosine. Preferably, dopamine antagonists should not interact with theα1 adrenergic receptor, as interactions with this G-coupled proteinreceptor give rise to types of hypotension.

The binding characteristics of examples of this patent for the D₂, D₄and α1 receptor subtypes are shown in Table 2.

TABLE 2 Compound Number D₂ K_(i) (nM) D₄ K_(i) (nM) α1 1 136 4 1095 2201 19 1735 4 50 9 >1 μM

Preferred compounds of the invention exhibit Ki values of less than 500nM at the dopamine D₄ receptor, more preferred compounds exhibit K_(i)values of less than 100 nM and most preferred compounds of the inventionexhibit K_(i) values of less than 20 nM. Preferred compounds of theinvention also exhibit greater than 20-fold selectivity for the dopamineD₄ receptor over the dopamine D₂ receptor; more preferred compounds ofthe invention exhibit greater than 100-fold selectivity for the dopamineD₄ receptor over the dopamine D₂ receptor.

Example 4 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention may be prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Tritium labeled probecompounds can also be prepared, when appropriate, by sodium borotritidereduction. Such preparations are also conveniently carried out as acustom radiolabeling by any of the suppliers listed in the precedingparagraph using the compound of the invention as substrate.

Example 4a Synthetic Scheme for the Preparation of the RadiolabledCompounds of the Invention

The above scheme, a modification of scheme I, represents a method forpreparation of radiolabeled probe compounds of the invention. Thissynthesis is carried out using ARC-802 Indole, [2-¹⁴C(U)], supplied byAmerican Radiolabeled Chemicals, Inc., St. Louis, Mo., as theradioisotope precursor.

Example 5 Use of Compounds of the Invention as Probes for DopamineReceptors in Cultured Cells and Tissue Samples

Receptor autoradiography (receptor mapping) of NK-3 or GABA_(A)receptors in cultured cells or tissue samples is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExample.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which in it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein A representsphenyl optionally substituted with up to four groups independentlyselected from halogen, hydroxy, amino, mono- ordi(C₁-C₆)hydrocarbylamino, aminosulfonyl, C₁-C₆hydrocarbylaminosulfonyl, di(C₁-C₆)hydrocarbylaminosulfonyl, cyano,nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C₁-C₆ hydrocarbyl,trifluoromethoxy, C₃-C₆ cyclohydrocarbyl, and C₁-C₆ alkoxy; R₅ and R₆are the same or different and represent hydrogen or C₁-C₆ hydrocarbyl;and R₂ represents hydrogen, halogen, hydroxy, amino, mono- ordi(C₁-C₆)hydrocarbylamino, aminosulfonyl, C₁-C₆hydrocarbylaminosulfonyl, di(C₁-C₆)hydrocarbylaminosulfonyl, cyano,nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C₁-C₆ hydrocarbyl,trifluoromethoxy, C₃-C₆ cyclohydrocarbyl, or C₁-C₆ alkoxy; and n is 0or
 1. 2. A compound according to claim 1, wherein R₂ is hydrogen,fluoro, chloro, or C₁-C₂ alkyl.
 3. A compound according to claim 2wherein A is a group of the formula:

where R₃ and R₄ independently represent hydrogen, halogen, hydroxy,amino, mono- or di(C₁-C₆)alkylamino, aminosulfonyl, C₁-C₆alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, cyano, nitro,cycloalkylalkyl, trifluoromethyl, C₁-C₆ alkyl, trifluoromethoxy, C₃-C₆,cycloalkyl, or C₁-C₆ alkoxy.
 4. A compound according to claim 3, whereinat least one of R₃ and R₄ is in the ortho or para position of the phenylring.
 5. A pharmaceutical composition comprising a compound according toclaim 1, together with at least one pharmaceutically acceptable carrieror excipient.
 6. “A method for the treatment of schizophrenia comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of claim 1.”
 7. “A method for thetreatment of Parkinson's disease comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound of claim 1.”
 8. “A method for the treatment of psychoticdepression comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound of claim 1.”9. “A method for the treatment of mania comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim 1.”
 10. “A method for the treatment of tardivedyskinesia comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound of claim 1.”